Genetic Instability of Microsatellite Loci in Primary Mediastinal B-cell Lymphoma

Context: Loss of heterozygosity (LOH) in STR loci, elevated microsatellite alteration at selected tetranucleotides (EMAST) and instability of mononucleotide tandem repeats (MSI - microsatellite instability) are intrinsic features of diverse tumor cells. For primary mediastinal B-cell lymphoma (PMBCL) these molecular factors to determine the prognosis of the disease have not been described yet. Objective: To analyze the frequency of LOH, EMAST, and MSI in tumor cells of PMBCL patients at diagnosis and to check possible association with disease features. Design: STR profiles of the DNA of tumor cells were analyzed on a cohort of 36 PMBCL patients undergoing treatment at the National Research Center for Hematology (Moscow, Russia). Setting: DNA was isolated from tumor biopsy samples taken at diagnosis. Control DNA samples were taken from the blood of patients in complete remission or from the buccal epithelium. STR-profiles for LOH and EMAST analysis were assessed by PCR with COrDIS Plus multiplex kit for amplification of 19 STR-markers and amelogenin loci (Gordiz Ltd, Russia). COrDIS MSI (BAT-25, BAT-26, NR-21, NR-24 and NR-27) kit was used for MSI testing. The fragment analysis was performed on ABI3130 Genetic Analyzer. Patients: Inclusion criteria: de novo diagnosed PMBCL patients. There were 10 males and 26 females, the median age at presentation was 30 years (range 21–61). Main outcome measures: Progression-free survival (PFS) and overall survival (OS) at 24 months from diagnosis were used to assess the independent impact of the genetic instability as a risk factor. Results: LOH was revealed in 21 out of 36 patients (58%). EMAST was found in 18 patients (50%); in 12 of them EMAST was accompanied by LOH, and in one by MSI. MSI was found in three patients only. OS and PFS were highest in the group with stable STR profile of a tumor, but not formally significant because of the small sample size. Conclusions: The high incidence of LOH and EMAST in PMBCL can cause standard therapy failure in a significant number of patients. EMAST as a variant of microsatellite instability might be useful for further consideration as a predictor of response to checkpoint inhibitor therapy.